Process for preparing 2-oxospiro{8 indoline-3,4{40 -thiochromans{9

ABSTRACT

6,7-Dihydro-12H(1)benzothiepino-(5,4-b)indole-5-oxides are utilized as precursors for making certain 2-oxospiro(indoline3,4&#39;&#39;-thiochroman)derivatives, of which the ester and nitrile derivatives are useful as inhibitors of gastric acid secretion and the acid derivatives are useful as precursors for making the ester derivatives.

E] rte States t [1 1 [11] 3 1 Paragamian June R8, 1974 PROCESS FOR PREP i [56] Reierences Cited THIOCHROMANS] 3,314,950 4/1967 Wei et al. 260/325 X [75] Inventor: Vasken Paragamian, Dresher, Pa. 73 Assignee: McNeil Laboratories, lnc., Fort Primwy Examiner-Joseph Narcavage Washington, p Attorney, Agent, or Firm-Salvatore R. Conte [22] Filed: July 21, 1972 ABSCT [2]] Appl. No.: 274,021

6,7-D1hydro-12H[ l ]benzoth1ep1no-[5,4-b]mdole-5- Related pp Data oxides are utilized as precursors for making certain 2- [62] Division of Ser. No. 137,043, April 23, 1971, Pat. oxospir0[indoline-3,4-thiochroman]derivatives, of

N ,4 which the ester and nitrile derivatives are useful as inhibitors of gastric acid secretion and the acid deriva- [52] US. Cl. 260/325 fives are useful as precursors for making the ester de- [5 Int. rivatives [58] Field of Search 260/325 2 Claims, No Drawings PROCESS FOR PREPARING 2-OXOSPIRO[INDOLINE-3,4-THIOCHROMANS] This is a divisional application of my co-pending application Ser. No. 137,043, filed Apr. 23, 1971, now US. Pat. No. 3,723,459.

This invention relates to certain novel organic compounds which may be structurally represented by the formulas:

and

wherein n is an integer from 1 to about 4, R and R" are each a member selected from the group consisting of hydrogen, halo, loweralkyl and loweralkoxy, and R is a member selected from the group consisting of CN, COOH and COO(loweralkyl). The compounds of formula (l-a) are denoted as 6,7-dihydro-l2-[(CH ),,-R']- l2H[ l ]benzothiepino[5,4-b]indole-5 oxides and those of formula (l-b) as l-[ (CH ),,-R']-2-oxospiro[indoline- 3,4'-thiochromans]. The former are useful precursors for making the latter.

As used herein, loweralkyl and loweralkoxy" may be straight or branch chained saturated hydrocarbons having from 1 to 5 ca r bon atoms, such as, for example,

methyl, ethyl, propyl, isopropyl, butyl, pentyl and the like alkyls, and, respectively, the corresponding alkoxys such as methoxy, ethoxy, propoxy, isopropoxy,

etc. The term halo" refers to iodo, bromo, chloro and fluoro. The formula (l-a) sulfoxide compounds are obtained by conventional sulfide-to-sulfoxide oxidation of thecorresponding 6,7-dihydrol 2-[ (CH ),,-R' l2H[ l ]benzothiepino[5,4-b]-indoles of formula (ll), for example, by treatment with sodium metaperiodate in a aqueous lower alkanol solvent or hydrogen peroxide in acetic acid as the oxidizing agent:

The sulfide precursors of formula (ll) may be prepared from the corresponding N-unsubstituted sulfides ofform ula (lll);

(III) Treatment of (III), preferably in the form of an alkali metal salt, with (a) a haloalkyl nitrile of the formula:

'halo-(Cl-l ),,-CN, or (b) a haloalkyl ester of the formula: halo-(CH ),,-COO(loweralkyl), wherein halo is preferably bromo or chloro and n is an integer from l .to about 4, or (c) acrylonitrile, affords the following N- substituted sulfides of formulallll (II-c) prepared by the following reaction scheme:

3 4 The foregoing reactions are preferably conducted in aprotic organic solvents. for example, an aromatic hy- R l 3 so drocarbon such as benzene, toluene, xylene and the i l like; an ether such as dioxane, tetrahydrofuran, dimeth- N/\ oxyethane and the like; and dimethylformamide 5 R (DMF). Temperatures of about 4080C. and reaction times of about 2-6 hours are generally suitable. P

The acid derivatives of formula (II), i.e., where Z T (CH ),,-COOI-I, are readily obtained by standard hy- I) drolysis, which may be effected with either acid or base to NaOHl [alkanul as catalyst, of the corresponding nitriles (ll-a) and Eton (my (ll-c) or esters (II-b). In turn, the acids (II-d) may be subjected to conventional esterification with a lower N80}; B B NM) alkanol in the Presence of a catalytic amount of an acid Q l such as HCI, H SO4 and the like to yield the correl N spending esters (II-b). Alternatively, the esters (ll-b) (CH1) may be obtained from the nitriles (II-a) and (ll-c) by n standard'nitrile-to-ester transformation procedures. COOH a. 2O wtu (II-a) (11-8) R TO Mk 1 The sulfides of formula (III), wherein R and R are (Ema N/\ liig fiol each hydrogen, are described in Aksanovtl et al., Zh. J; lows: Obshch. Khim., 34, 3375 (1964). In general, the for- (IH) R alkanol mula (Ill) sulfides may be prepared by reacting an ap- $0011 {lower alkanol proprlate thlophenolof formula (VIII) with y butyrodry HCI lactone (IX) according to the method described by (Hd) (1H) Traynelis et al., J. Org, Chem, 26, 2728 (I961), to

yield the 'y-phenylmercaptobutyric acid of formula (X) The formula (La) c mp ds m b lt i l which is then subjected to ring-closure under acidic dehydrating conditions, for example, by heating with a. treating the N-unsubstituted sulfoxide of formula polyphosphoric acid, and then reacting the thus- (lv), preferably in the form of an alkali metal salt, said Obtained 5-0X0-2,3,4,5-tetrahydr0-benZ0[ blthiepirl 0f sulfoxide being obtained by the previously described formula with an pp p phenylhydfaline Of sulfide-to-sulfoxide oxidation of the corresponding N- 5 formula which y be in the form of a b timr d lfid (In), i h an appropriate 1 1 drochloride salt, under Fischer indole synthesis condi k i il f h f l h 1 (CH CN or with an tions, for example, with dry HCl in ethanol. to yield the appropriate haloalkyl ester of the formula: i Q QPPP Q 9f mq (m):

halo-(CH ),,-COO(loweralkyl),or with acrylonitrile, to 40 R O m yield the corresponding N-(Cl-I ),,-CN (V), or N-(CH ),,-COO(loweralltyl) (VI), or N-(Clhh-CN (V-a), derivatives, respectively; (vnr (1X) b. hydrolyzing said nitrile function of (V) to the acid R form (VII) under alkaline conditions; W i p osphorie c. hydrolyzing the ester function (Vl) to the acid. SOHICILCHCOOH T form (VII) under alkaline conditions; and (X) d. esterifying the acid (VII) with a lower alkanol to 0 R obtain the ester (VI). l

R I S S O l (XII) (In) R l l R l l s N N H W 7 M a E @114 ii H R 1 S a a The formula (I-a) compounds are useful precursors (In) '5 (W) for making the compounds of formula (l-b). The for- H H l 7 7 J k V ii '7 u mation of the spiro type latter compounds may be acwv? complished by several routes, for example: i i g //l q a. by treating the formula (l-a) starting material with so 8 s a small amount of an acid such as HCI and HBr, gener- R l o E R l 1 ally from about 2050 percent of the molecular equiva- ,s \N/\\ lent of acid based on the molar amount of the (l-a) pre- L 5 E cursor employed in a suitable anhydrous aprotlc sol- R" Z (O R" vent, such as, for example, an aromatic hydrocarbon. 5 N e.g., benzene, toluene, xylene and the like, or an ether (V) (Va) suchasdioxane, diethylether, dimethoxy ethane, tetrahydrofuran and the like. Alternatively, a system may be employed consisting of from about 0.] to about 0.2 molecular equivalents of concentrated H 80 in a lower alkanoic solvent, preferably absolute methanol or ethanol, in which case, however, lower yields of the desired 5 (l-b) compounds are obtained. In general, ambient temperatures may be employed although elevated temperatures can be used to enhance the rate of reaction;

b. by treating the formula (l-a) starting material with hydrochloric or hydrobromic aqueous acid solution (10 20 percent) under reflux conditions; and

c. by treating the formula (l-a) starting material with from 1 to about 2 molecular equivalents of either acetyl chloride, oxalyl chloride or acetic acid anhydride in an anhydrous aprotic solvent such as previously mentioned for route (a) and, in addition, a halogenated lower alkane, e.g., dichloroethane, chloroform, dichloromethane and the like. With acetyl chloride and oxalyl chloride, ambient temperatures may be employed although elevated temperatures can be used to enhance the rate of reaction, and with acetic acid anhydride, temperatures of about 8090C. are preferred.

The foregoing (l-a)-to-(l-b) transformation proce-. dures may be schematically exemplified as follows:

Route (a):

Baby. 1161 benzene chloride or oxalyl chloride. Lesser yields are obtained with acetic acid anhydride.

With regard to route (a), it should be borne in mind that when the formula (l-a) precursor is an ester, that is, when R is COO(loweralkyl), and a lower alkanol is employed as the solvent, then transesterification may occur if the loweralkyl hydrocarbon of the ester function and the alkanol are different. Likewise, when the formula (l-a) precursor is an acid, that is, when R is COOH, and a lower alkanol is employed as the solvent, t h en esterification will occur.

The foregoing (l-a)-to-(l-b) transformation procedures are believed to be novel methods and, as such, they constitute an additional feature of this invention.

An alternative method of the esters acids of formula (l-b) is from the corresponding nitriles of formula (Xlll). Hydrolysis of the nitrile function to the acid form according to standard nitrile-to-acid procedures, or transformation of the nitrile function to the ester form according to standard nitrile-to-ester procedures, affords the corresponding acids (XIV) and es ters (XV). The acids in turn may be esterified with an rs q sllrststkaaqtt9.n lslillss zg ve The preferred method of making the formula (l-b) compounds is by way of route (c) using either acetyl 0 esters (XV). Likewise, hydrolysis of the latter affords the esp nd n a id (Xl alkanol dry H01 n 0 (lower alkyl) tobutyric acid.

Accordingly, the formula (XIII) nitriles are useful precursors for making the acids and esters of formula (I-b). The formula (XIV) acids are useful precursors for making the formula (XV) esters. In addition, the formula (XIII) nitriles and the formula (XV) esters, which are the preferred embodiments of the present invention, have been found to possess pharmacological activity as inhibitors of gastric acid secretion in pyloricligated rats [according to the method of Shay et al., Gastroenterology, 26, 906, 1954)] at doses of 50-200 mg/kg body weight i.p., which activity is an indication of usefulness in a number of gastrointestinal disorders such as, for example, ulcers.

The preferred compounds of this invention are those wherein the substituents R and R", when other than hydrogen, are in the 9-position and 2-position, respectively, of the formula (I-a) compounds; and in the 5- position and 6-position, respectively, of the formula (I-b) compounds:

The following examples are presented in order to illustrate, but not to limit the scope of, the subject invention.

EXAMPLE I @somcmomoooa A. To a solution of potassium ethoxide prepared from potassium (7.8 g., 0.20 g.-atom) and 50 ml. of absolute ethanol is added a solution of thiophenol (22 g., 0.20 mole) in 150 ml. of diethyl carbitol. After the ethanol is removed by distillation, 'y-butyrolactone (l8 g, 0.21 mole) in 100 ml. of diethyl carbitol is added slowly and the resulting slurry heated with rapid stirring for 3 hr. at l70l75C. To the cooled reaction mixture is added 300 ml. of water and the solution washed with two 300ml. portions of ether. The aqueous solution is acidified with hydrochloric acid; after the resulting precipitate is collected and dried, crystallization from petroleum ether (b.p. 6080C.) gives 36 g. (92%) of 'y-phenylmercaptobutyric acid, m.p. 68-69C.

B. The procedure of Example I-A may be followed to prepare the compounds of formula (X) by employing an appropriate thiophenol of formula (VIII) as the starting material. For example, by repeating the procedure, except that an equivalent quantity each of 4- chloro-thiophenol, 4-br0mo-thiophenol, 4-methylthiophenol and 4-methoxy-thiophenol are used in place of the thiophenol used therein, there are obtained, as respective products, the 4-chlor0, 4'-bromo, 4'-methyl and 4'-methoxy derivatives of 'y-phenylmercap- EXAMPLE II A. To polyphosphoric acid 1 kg.) at C. is added 98 g. (0.5 mole) of y-phenylmercaptobutyric acid and the resulting mixture is heated at 100C. for 1 hr., poured onto ice and extracted with benzene. The benzene solution is washed with dilute sodium hydroxide solution, dried and concentrated. The residual oil is distilled to give about 77 g. of 5-oxo-2.3,4,5-tetrahy- EXAMPLE III (III) A. A 35.6 g. sample of 5-oxo-2,3,4,5-tetrahydrobenzolb lthiepin and a 29 gv sample of phenylhydrazine hydrochloride are dissolved in 450 ml. of ethanol and the resulting solution is saturated with hydrogen chloride and refluxed for 1 hr. After cooling, the separated solid is collected by filtration and the filtrate is concentrated to give a solid, 6,7-dihydro-l 2H[ 1 lbenzothiepino[5.4- blindole. which is recrystallized from methanol. yielding about 29 g. of white crystals, m.p. l55l56C.

B. The compounds of formula (III) may be prepared in accordance with the procedure outlined in Example Ill-A. For example, by using as starting materials an equivalent amount of an appropriate phenylhydrazine hydrochloride of formula (XII) and an equivalent amount of an appropriate benzothiepin of formula (XI), the following respective products are obtained: 2-chloro-6.7-dihydro- 1 2H[ 1 ]benzothiepino[ 5,4- blindole;

2,9-dichloro-6.7-dihydro- 1 2H[ l ]benzothiepino[ 5,4

blindole;

9-methyl-6,7-dihydro- 1 2H[ 1 lbenzothiepino[5,4- blindole;

9-methoxy-6,7-dihydro- 1 2H[ 1 ]benzothiepino[5,4- b]indole;

2-bromo-9-methoxy-6,7-dihydro- 1 2H[ l lbenzothiepinol 5 ,4-blindole; 2-methoxy-9-methyl-6,7-dihydro- 1 2H[ 1 ]benzothiepinol5 ,4-blindole;

2-methyl-6,7-dihydro-l 2H[ 1 ]benzothiepino[ 5 ,4- b]indole; and

2,9-dimethyl-6,7-dihydro- 1 2H[ 1 ]benzothiepino[ 5 ,4- b] indole.

A. 6,7-Dihydro- 1 2H[ 1 ]benzothiepino[5,4-b]indole- -oxide: A 75 g. sample of 6,7-dihydro-l2H[l]benzothiepino-[5,4-b]indole (0.3 mole) is combined with 70 g. (0.33 mole) of sodium metaperiodate in l 100 ml. of methanol and 100 ml. of water and the resulting mixture is stirred at room temperature for 18 hrs. The mixture is then warmed to reflux and heated for 3 hrs. and then cooled. The separated solid is filtered and washed repeatedly with water and then dried. The product, 6,7- dihydro-l 2H[ 1 ]benzothiepino[ 5,4-b1indole-5-oxide, about 75 g. in the fonn of white crystals, melts at 202-205C. After recrystallization from ethanol, the m.p. is 203-205C.

B. The sulfide-to-sulfoxide oxidation process of Example lV-A may be followed in preparing the compounds of formula (IV). For example, by so oxidizing an equivalent amount of each sulfide obtained in Example lIl-B, the corresponding sulfoxides are respectively obtained.

EXAMPLE V Equivalent amounts of 6,7-dihydro-l2H[ l ]benzothiepino[ 5,4-b]indole and sodium hydride are mixed in dimethylformamide (DMF) at room temperature. One equivalent of 2-bromo-ethyl cyanide in DMF is added to the reaction mixture which is heated at 5060C. for 4 hours and then cooled, diluted with 2 percent hydrochloric acid solution and extracted with methylene chloride. Concentration of the extract yields the product, 6,7-dihydrol 2-(2-cyanoethyl l 2H[ 1 ]benzothiepino[5,4-b]indole, which is purified by recrystallization from isopropyl alcohol.

EXAMPLE VI The procedure of Example V is repeated except that an equivalent amount each of chloromethyl cyanide, 3-chloropropyl cyanide and 4-bromo-butyl cyanide is substituted for the 2-bromo-ethyl cyanide used therein to yield, as respective products, the corresponding 12- cyanomethyl, l2-(3-cyanopropyl) and 12-(4- cyanobutyl) derivatives of 6,7-dihydro-l2H[l]benzothiepino[ 5,4-b]indole.

EXAMPLE Vll By following the procedure of Example V, except that an equivalent quantity of the appropriate benzothiepino[5.4-b]-indole obtained in Example "I and an equivalent quantity of the appropriate w-halo-cyanide are used as starting materials, the following respective products may be obtained: 2-chloro-6,7-dihydrol 2-( 2-cyanoethyl l2H[ l ]benzothiepino-[ 5 ,4-b]indole; 2,9-dichloro-6,7-dihydrol 2-cyanomethyll2H[ l ]benzothiepino-[5,4-b]indole; 9-methy16,7-dihydro-l2-( 3-cyanopropyl)- 12H[ 1 ]benzothiepino-[5,4-b]indole; 9-methoxy-6,7- dihydro-l 2-cyanomethyl- 1 2H[ 1 ]benzothiepino-[ 5 ,4- b]indole;

W 2-bromo-9-methoxy-6,7-dihydrol 2-(2-cyanoethyl l2H[ l ]benzothiepino[5,4-b]indole; 2-methoxy-9-methyl-6,7-dihydrol 2-( 2-cyanoethyl 12H 1 ]benzothiepino[5,4-b]indole; 2-methyl-6,7-dihydrol 2-( 4-cyanobutyl 12H[ 1 ]benzothiepino-[5,4-b]indole; and 2,9-dimethyl-6,7-dihydrol 2-( 2-cyanoethyl l2H[ l ]benzothiepino-[5,4-b]indole.

EXAMPLE Vlll Equivalent amounts of 6,7-dihydro-l2H[ l ]benzothiepino-[5,4-b]indole and sodium hydride are mixed in dimethylformamide (DMF) at room temperature. One equivalent of ethyl bromoacetate in DMF is added to the reaction mixture which is heated at 5060C. for 4 hours and then cooled, diluted with 2 percent hydrochloric acid solution and extracted with methylene chloride. Concentration of the extract yields the product, 6,7-dihydro-l2-(2-carbethoxymethyl)- l2H[1lbenzothiepino[5,4-b]indole, which is purified by recrystallization from isopropyl alcohol.

EXAMPLE IX corresponding l2-carbethoxymethyl derivatives of each of the Example lll-B products, respectively.

EXAMPLE XI 10 Grams of 6,7-dihydro-l2-(2-cyanoethyl)-l2H[ l benzothiepino[5,4-blindole is mixed with 2.7 g. sodium hydroxide in 80 ml. of aqueous ethanol percent) and refluxed for 5 hours. The reaction mixture is then concentrated to about one-fifth of its original volume, then diluted with water up to original volume, acidified with dilute hydrochloric acid solution and the product extracted with chloroform. The chloroform extract is concentrated and the crude product is recrystallized from ethanol to give pure 6,7-dihydro-l2-( 2- carboxyethyl)- l 2H[ 1 ]benzothiepino-[5,4-blindole, mp. 192C.

EXAMPLE XII The nitrile-to-acid hydrolysis procedure of Example X] may be followed to prepare the 6,7-dihydro-l2-(wcarboxyalkyl)-l2H[ l lbenzothiepino[5,4-b1indoles of formula (ll-d). For example, by utilizing an equivalent amount of each nitrile obtained in Examples VI and Vll as the starting material to be hydrolyzed, the corresponding IZ-(w-carboxyalkyl) acids are obtained, re-

spectively.

11 EXAMPLE XIII 6,7-Dihydrol 2-( Z-cyanoethyl 1 2H[ 1 lbenzothiepino- [5,4-b1indole-5-oxide A 30 g. sample of 6,7-dihydro-l2-(2-cyanoethyl)- l2H[l]benzothiepino[5,4-b]indole and 24 g. of sodium metaperiodate are refluxed in 300 ml. of aqueous methanol for two hours. After cooling, the separated solids are filtered, washed repeatedly with water, and dried to give about 27 g. of white crystals, 6,7-dihydrl 2-( Z-cyanoethyl l 2I-I{ l ]benz0thiepino[ ,4-9 indole- S-oxide, m.p. l90l92C.

EXAMPLE XIV The sulfide-to-sulfoxide oxidation procedures of either Example IV-A or Example XIII may be followed to prepare the compounds of formula (l-a). For example, by so oxidizing an equivalent amount of an appropriate sulfide of formula (II), the following sulfoxides are obtained as respective products:

6,7-Dihydrol 2-( Z-cyanoethyl l 2H{ 1 lbenzothiepino- [5 ,4-b]indole-5-oxide A 50 g. sample of 6,7-dihydro-l2[ l 1- benzothiepinol5,4-b]indole-5-oxide (0.1 8 mole) is suspended in 300 ml. of acrylonitrile and drops of trimethyl benzyl ammonium hydroxide (TRITON B) are added cautiously and slowly. The mixture gradually warms up and becomes homogeneous. It is allowed to stand overnight and the separated solid is filtered off, washed with a small amount of acrylonitrile, then ether. and dried. The filtrates are concentrated, triturated with chloroform and insoluble solids are removed by filtration. The chloroform filtrates are concentrated and the residue gives about 14 g. of 6.7-dihydro-l2-(2- cyanoethyl)- 1 2H[ 1 l-benzothiepinol 5 ,4-b]indole-5 oxide, total yield 45 g. (75%), mp. l92l93C.

EXAMPLE XVI The procedure of Example XV is repeated, except that an equivalent quantity of each sulfoxide obtained in Example lV-B is substituted for the 6,7-dihydrol2H[ l ]benzothiepino-[ 5,4-b]indole-5-oxide used therein, to yield, as respective products, the following l2-( Z-cyanoethyl) sulfoxides of formula (La);

EXAMPLE XVII CHgC 0 H A. 6.7-Dihydro l 2-( Z-carboxyethyl lZHE l lbenzothiepinol5.4-blindole-5-oxide A 35.5 g. (O.ll mole) sample of 6.7-dihydro-l2-(l cyanoethyl 1 2H[ 1 !benzothiepino[ 5.4-b l-indole-S- oxide is hydrolyzed by refluxing in 500 ml. of aqueous ethanol for 6 hrs. in the presence of l() g. (025 mole) of sodium hydroxide. After concentration. the mixture is diluted with water and extracted with chloroform. The aqueous layer is acidified with dilute HCl and extracted with chloroform. The combined chloroform layers in turn are extracted with potassium car bonate solution and after acidification of the latter the product is taken up in chloroform. Concentration of the chloroform extract gives a solid, 6.7-dihydro-l 2-( 2 carboxyethyl)-l2H[ l ]benzothiepino[5.4-hlindole-5- oxide. which is recrystallized from ethanol. as white crystals, mp. l9l-l93C B. The hydrolysis procedure of Example XVII-A is repeated. except that an equivalent quantity of each l2-(2-cyanoethyl) sulfoxide obtained in Example XIV and Example XVI is used as the starting material, to yield, as respective products. the corresponding lZ-(Z- carboxyethyl) sulfoxides.

EXAMPLE Xv'lll CHgC- OrEt A. 6,7-Dihydroi 2-( 2-carbethoxyethyl l2H[l lbenzothiepinol 5,4-hiindole-5 oxide A 9.1 g. of 6.7-dihydro-l2-(2-carboxyethyl)- l2H[ l lbenzothiepinol5.4-blindole-5-oxide is esterilied by refluxing in ethanol. in the presence of a few drops of concentrated sulfuric acid for 4 hrs. The mixture is concentrated and the residue taken up in chloroform, washed with potassium carbonate solution and concentrated to give a solid, 6.7-dihydro-l2-(2- carbethoxyethyl 1 2H[ 1 lbenzothiepino-l 5,4-b1indole- 13 EXAMPLE XIX memory A. l-( Z-Cyanoethyl )-2-oxospir0[ indoline-3 ,4 thiochroman] A 6 g. (0.019 mole) sample of 6,7-dihydro-l2-(2- cyanoethyl 1 2H-[ 1 ]benzothiepino[ 5,4-b]indole-5- oxide is refluxed for 5 hrs. with 75 ml. of 18 percent hydrochloric acid. The separated solid is filtered, stirred in chloroform with alumina and charcoal, filtered and the chloroform solution concentrated and then passed through acid-washed alumina with chloroform and concentrated to give l-( 2-cyanoethyl )-2- oxospirolindoline-3,4-thiochroman] as white crystals, m.p. l85-l86C.

B. The procedure of Example XIX-A is followed to prepare those compounds of formula (I-b) wherein R is CN. For example, by utilizing, as the formula (l-a) nitrile precursor, an equivalent amount of each of the nitriles described in Examples XIV and XVI, the corresponding nitrilespiro compound of formula (l-b) is respectively obtained.

EXAMPLE XX l CHgCHzC OgEt 2-oxospiro{indoline-3,4-thiochroman l -oxide in benzene is treated with 0.2 ml. of acetyl chloride at room temperature for 4 hrs. Concentration yields the solid product, ethyl Zoxospiro-[indoline- 3 ,4'-thiochroman l -propionate.

C. The procedures of Example XX-A and Example XX-B may each be followed to prepare those compounds of formula (I-b) wherein R is COO(loweralkyl). For example, by utilizing, as the formula (I-a) ester precursor, an equivalent amount of each of the esters described in Examples XIV and XVIII, the corresponding ester-spiro compound of formula (l-b) is respectivell ainsaw- M EXAMPLE XXI 10 A. 2-Oxospiro[indoline-3.4'-thiochroman]-lpropionic acid A 7.7 g. (0.021 mole) sample of ethyl 2- oxospiro[indoline-3,4'-thiochroman l -propionate is hydrolyzed by refluxing in aqueous ethanol in the presence of 0.9 g. (0.022 mole) ofsodium hydroxide for 4 /2 hrs. After concentration and dilution with water, the solution is extracted with ether and acidified, and then extracted with chloroform. Concentration of the chloroform extract gives an oil which crystallizes in ethyl 'acetate-cyclohexane. Recrystallization from the same solvents yields 2-oxospiro[ indoline-3,4'-thiochroman]- l-propionic acid as offwhite crystals, m.p. l44-l46C. (V,,,,, 1720, 1700, 1660, i600 cm") I B. The foregoing ester-to-acid hydrolysis procedure may be used to prepare the acid-spiro compounds of formula (l-b). For example, by repeating the hydrolysis procedure of Example XXI-A, except that an equivalent quantity of each ester obtained in Example XX-C is used as the starting ester to be hydrolyzed. there are obtained, as respective products, the corresponding acid-spiro compounds of formula (l-b).

This example illustrates an esterification procedure which can be followed for the purpose of converting the acids of formula (XIV) into the corresponding esters of formula (XV) by treatment of the former with an appropriate lower alkanol.

A 10 percent solution of 2-oxospiro[indoline-3,4- thiochromanl-l-propionic acid in ethanol is refluxed for 4 hours in the presence of a catalytic amount of a mineral acid (such as concentrated sulfuric acid or dry hydrogen chloride).v After concentration to one-third of the original volume, the solution is chilled and the product, ethyl 2-oxospiro[indoline-3,4-thiochroman]- l-propionate, precipitates and is collected by filtration wherein n is an integer from 1 to about 4, R and R" are each a member selected from the group consisting of hydrogen, halo, loweralkyl and loweralkoxy, and R is a member selected from the group consisting of CN,

COOH and COO(loweralkyl), which comprises treating a 6,7-dihydro-l2H[ l ]benzothiepino[ 5,4-bl-indole- S-oxide of the formula:

aim R wherein n is an integer from l to about 4, R and R" are each a member selected from the group consisting of hydrogen, halo, loweralkyl and loweralkoxy, and R is a member selected from the group consisting of CN, COOH and COO(loweralkyl), which comprises treating a 6,7-dihydro-l2Hl l ]benzothiepino[5,4-b1-indole- S-oxide of the formula:

R we

wherein FIIRIR' 25H R are as previously described, with from 1 to about 2 molecular equivalents of acetic acid anhydride at 90C. in an anhydrous aprotic solvent.

W105? UNITED STATES PATENT OFFICE 56 CERTIFICATE OF CORRECTION Patent No. 3, 3 Dated June 18, 97

I entofl Vasken Paragamian It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 2 In the reaction scheme (c) at the bottom of the page, the portion shown as:

NaH should. be corrected. to read. KOH

benzene benzene Column 7 In Formula (I-a, preferred), the positioning of the R" substituent was misplaced. In addition, the R substituent was not included. The structural formula should. be corrected. accordingly to appear as follows:

(CH )n l and Rll

(I-a, preferred) Signed and sealed this 6th day of May 1975.

(SEAL) AtteSt:

C. MARSHALL DANN RUTH C. MASON Commissioner of Patents Attesting Officer and Trademarks 

2. A method of preparing a 2-oxospiro(indoline-3,4''-thiochroman) derivative of the formula: 